Management in Expert Referral Centers and Multidisciplinary Teams

Given the heterogeneity and low incidence of this malignancy, management of gynecological sarcoma must be carried out in multidisciplinary teams within reference centers.5 Because of their rarity, sarcomas are often initially misrecognized, misdiagnosed, and as a consequence not treated according to clinical practice guidelines.6 There is a large body of scientific evidence demonstrating how the initial management of the disease impacts on patients’ survival, both on the local and distant control of the disease.7 A recent study of the French sarcoma group (NETSARC) including almost 30 000 patients with soft tissue sarcomas and visceral sarcomas demonstrated the correlation between sarcoma management in a referral institution and patients’ survival.7 The complete resection rate R0 is around 50% when patients undergo surgery in a non-expert sarcoma center, and the R2 resection rate is more than twice than that of surgeons working in referral centers. Moreover, patients treated outside referral institutions have higher relapse rates, decreased survival outcome, and have an excess cost associated with their suboptimal treatment that is estimated to be approximately 60 million euros over the study period.7 Because sarcomas are often managed with multimodal treatments, a multidisciplinary approach in the case of suspected gynecological soft tissue sarcoma or visceral sarcoma is mandatory, involving specialized radiologists and nuclear medicine specialists, pathologists, surgical oncologists (or organ-based specialists), medical oncologists, and radiation oncologists. Once there is a sarcoma suspicion on imaging workup, a percutaneous biopsy must be performed for soft tissue sarcoma frequently using a transgluteal approach to avoid peritoneal spreading.6 In cases of localized tumor, transvaginal or transrectal biopsies (eg, by echoendoscopy) should be avoided to prevent contamination.

Radiological expertize is also essential to guide the pathologist with certain rare tumors such as deep angiomyomas or suspicious myometrial tumors.

Imaging

For primary pelvic sarcomas, MRI is the best imaging modality. MRI evaluation is essential to avoid morcellation, piecemeal resection, or inappropriate surgery in cases of uterine tumors with leiomyosarcoma radiological features. Pelvic MRI requires a specific protocol, including T2-weighted imaging, a T1 sequence (to search for hemorrhage), and diffusion-weighted imaging (DWI) to calculate the apparent diffusion coefficient (ADC) mapping. MRI accuracy is around 88–95% for detecting uterine leiomyosarcoma, with sensitivity of 83–100% and specificity of 88–100%. Abdominal T2 sequence up to the renal veins should be performed to evaluate para-aortic lymph node metastasis. An international consensus has recently been published defining the terms with a strong association in support of leiomyosarcoma diagnosis.8 Several algorithms have been published to help to differentiate atypical leiomyomas from uterine sarcomas on MRI but with a non-negligible false-negative rate.

CT is recommended for staging purposes, including thorax evaluation. Thorax assessment is mandatory as pulmonary metastases are the most frequent extra-abdominal location of gynecological sarcomas. More than 50% of leiomyosarcomas have pulmonary metastases at diagnosis.9 Liver and peritoneal metastasis are rare except for myxoid liposarcoma and leiomyosarcoma. Regional lymph node metastases are usually rare (fewer than 1%), but are frequently found in cases of synovialosarcoma, epithelioid sarcoma, clear-cell sarcoma, angiosarcoma, and endometrial stroma sarcoma.

CT is recommended for staging purposes, for lymph node assessment, but also for detecting calcifications in certain types of sarcomas. It is useful when considering a scan-guided biopsy.5

Fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT can be considered at the diagnostic phase, to guide the interventional radiologist in particular in cases of a necrotic tumor to target the biopsy on the most relevant area. PET/CT can also be used to search for metastasis more accessible to biopsy.5

Pre-operative Biopsy

Pre-operative biopsies, following appropriate imaging assessment, represent the cornerstone for sarcoma diagnosis including microscopy and biomolecular analysis. Frozen section at the time of the surgery is not encouraged because of the discrepancy rate, the underestimation of the tumor malignancy, and interference with adequate pathological processing.10

In suspicious gynecological mesenchymal tumors, several situations must be considered depending to the location of the tumor. Biopsies should always be carried out by a radiologist or surgeon in an expert center.5 A pathological expert validation is necessary for all cases, especially when the biopsy is performed outside of reference centers.

Cases of Pelvic Soft Tissue Tumor

The standard approach for pelvic soft tissue tumor diagnosis consists of multiple (with at least five to eight) core needle biopsies, using coaxial 14 G needles guided by CT scan or ultrasonography. Biopsies must be taken from a tissue part of the tumor and not from a necrotic area. The quantity of material taken must allow for surgical pathological analysis, including hematoxylin and eosin (H&E), immunohistochemistry, and molecular analyses, including next-generation sequencing, fluorescence in situ hybridization, or RNA sequencing, and comparative genomic hybridization, employed together to achieve a diagnosis and provide prognostic and theragnostic insights (Figures 1 and 2).4

To make the diagnosis of sarcomas, the conventional H&E staining technique is the first step to identify cellular differentiation, histological malignancy criteria, including atypia, mitotic activity, and necrosis, and to establish the histological type according to WHO 2020.

This approach is complemented by immunohistochemical panel, confirming histological types through cellular differentiation such as muscular, adipose, vascular, mesenchyma differentiation, and identifying molecular alterations, quickly and cost-effectively (p53, Rb, beta-catenin, STAT6, among others).

Additionally, molecular studies, such as next-generation sequencing for mutation detection, fluorescence in situ hybridization or RNA sequencing for the identification of fusion transcripts, and comparative genomic hybridization for evaluating copy number variations, can be performed. These analyses, sometimes essential for diagnosis, are expensive and are only available in specialized centers.

Remember that the biopsy method must be planned in consultation between the surgeon and the radiologist after multidisciplinary discussion. The biopsy tract will be removed by the definitive surgery. The biopsy entrance point can be tattooed for the same reason.5

Excisional or open surgical biopsy should be avoided because of the risk of tumor spreading, surgical contamination, and bleeding, which could lead to a change in the final surgical strategy.

Cases of Suspicious Myometrial Tumors

Uterine myometrial tumors are benign in most cases, with an estimated cumulative incidence of over 70% to 80% of women aged 50 years.11 One-third of them are conservatively treated by myomectomy and minimal invasive surgery. Both the American College of Obstetricians and Gynecologists (ACOG) and the American Association of Gynecologic Laparoscopists (AAGL) have released statements advocating for a minimal invasive approach to hysterectomy for benign indications.12 13 Compared with an abdominal approach, minimal invasive surgery decreases post-operative pain, wound complications, blood loss, hospital stay duration, and recovery time.14 Among these women, the reported prevalence of unsuspected sarcoma at surgery ranges from 1/10 000 to 1/352 depending on the inclusion criteria of different publications.8 15 MRI criteria and diagnostic algorithms do not allow discrimination with the greatest accuracy of leiomyomas, smooth-muscle tumors with uncertain malignancy potential (STUMPs), and leiomyosarcomas.

Despite advances in imaging, the risk of inappropriate surgery remains approximately 1/400, with an unacceptable loss of chance of survival in the case of myomectomy, which should be considered as a piecemeal resection.16 Re-operation does not give the same prognosis. Conversely, conservative uterine surgery for fertility purposes is offered to women of childbearing age with a leiomyoma for whom it is not acceptable to systematically perform a hysterectomy in the event of suspicion on MRI. It is therefore necessary to have histological information prior to myomectomy and avoid any oncological risk. In most cases, endometrial biopsies have a low predictive value in diagnosis of myometrial sarcoma compared with epithelial uterine malignancies17

Diagnostic management strategy was radically changed in 2023, following the publication by the Curie Institute (Paris) team of a preliminary study leading to a change in clinical practice.18 The authors demonstrated the diagnostic performance of a uterine percutaneous approach using coaxial core needle biopsy guided by ultrasonography under local anesthesia in an outpatient setting. Pathology examination included expert morphological assessment with immunohistochemistry analysis and array-comparative genomic hybridization analyses (Figure 1).

This approach presents two main limitations. The first is the risk of peritoneal spreading. This theoretical risk will in any case be less damaging than morcellation or piecemeal resection (myomectomy). In addition, the percutaneous approach has been published in gastrointestinal stromal tumors, with the same theoretical risk of peritoneal dissemination. Despite the transperitoneal approach for this type of sarcoma, there is no reported increase in the recurrence rate. The second limitation is the histological diagnostic accuracy using microscopic biopsy material. In this study, all biopsies were analyzed by an expert pathologist using microscopic and comparative genomic hybridization analyses according to Croce’s previous publications.19 The diagnostic accuracy is 100%. The sensibility, specificity, and negative predictive value were 100%, 100%, and 100%, respectively. A high genomic index was associated with malignancy. No dissemination was found at the time of the surgery. These results have modified the diagnostic management of patients planned for a myomectomy or a surgery with morcellation in France, whose omission can have dramatic consequences.

After this practice-changing publication, percutaneous biopsies with microscopic and comparative genomic hybridization analysis are included in the 2023 recommendations within the framework of the French Sarcoma Group (NETSARC+) and Malignant Rare Gynecological Tumors (TMRG) networks, in the management of patients with an indication of myomectomy or morcellation.20 If surgery with hysterectomy, a fortiori by laparotomy, is planned, the percutaneous biopsy may be omitted.

Cases of Suspicious Ovarian Tumors

Ovarian sarcomas are a very rare entity comprizing only 1% of ovarian tumors.21 Most published series of ovarian sarcomas include carcinosarcomas, which are now managed as epithelial ovarian tumors. The most common histotypes found are leiomyosarcoma, fibrosarcoma, and rhabdomyosarcoma. Differential diagnosis with ovarian metastasis from another sarcoma (Ewing sarcoma, uterine endometrioid stromal sarcoma) must be considered. Regarding surgical treatment of primary ovarian sarcomas, up to now there are no prospective studies to define management recommendations for these rare entities. The management of an ovarian tumor suggestive of sarcoma is similar to epithelial ovarian tumors, as imaging is not specific. Diagnostic surgery is most often required. Using frozen section it is difficult to distinguish sarcoma from a carcinosarcoma. For early stages, surgery including total hysterectomy and bilateral salpingo-oophorectomy is the mainstay of treatment. Tumor debulking should be considered/performed for advanced-stage disease.

Standardized Pathological Reporting

The pathological report for gynecological sarcomas should comprehensively encompass specific details, as recommended by both the College of American Pathologists and the International Collaboration on Cancer Reporting (ICCR). This report should contain the following critical information: operative procedure and specimen integrity, tumor site, maximum tumor size, histological type and grade, extent of invasion and lymphovascular invasion, margins status, TNM (Tumor, Node, Metastasis), and International Federation of Gynecology and Obstetrics (FIGO) staging.

Staging and Risk Assessment

CT is recommended for staging purposes, including thorax evaluation. Pulmonary metastases are frequent in case of sarcoma. More than 50% of leiomyosarcomas have pulmonary metastases at diagnosis. Liver and peritoneal metastasis are rare except for myxoid liposarcoma and leiomyosarcoma. Regional lymph node metastases are usually rare (fewer than 1%), but are frequently found in cases of synovialosarcoma, epithelioid sarcoma, clear-cell sarcoma, angiosarcoma, and endometrial stroma sarcoma.

FDG-PET/CT Use in Aggressive Tumors Seeking Lung or Bone Metastasis

Some promising consensus molecular classifications with prognostic relevance have been developed, but they are not used in daily practice. Developed to assess metastatic risk in soft tissue sarcomas, the Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity.22–24 CINSARC has weak prognostic power in high-risk, localized soft tissue sarcoma treated with neoadjuvant chemotherapy. CINSARC signature is being evaluated in a clinical research trial to guide the initiation of adjuvant chemotherapy in uterine leiomyosarcomas (NCT04307277).